Project Abstract Pancreatitis is an inflammatory disease of the pancreas causing significant morbidity, mortality and hospitalization. Studies suggest that pancreatitis is also a risk factor for pancreatic cancer. There is no specific therapy available for pancreatitis. One of the major symptoms for pancreatitis, whether acute or chronic is severe pain and treatment strategies include pain management with narcotics. Despite their prevalent use as analgesics in pancreatitis, the effect of opioids on the severity of the disease and its progression remain unclear. Our published data suggest that therapeutic use of morphine in acute pancreatitis (AP) has profound effect on disease progression and regenerative ability of the pancreas. Furthermore, our preliminary studies suggest that therapeutic morphine treatment leads to increased severity of chronic pancreatitis (CP). These results are highly significant as they suggest that morphine treatment of patients with AP may be making them more susceptible to a severe course or likelihood of developing CP. Similarly, treatment of patients with recurrent acute pancreatitis may make them more likely to evolve into CP. The mechanism by which morphine impacts severity of pancreatitis is not known. In addition to its immune-modulatory role, morphine has been implicated in causing dysbiosis. Modulation of microbiome has been shown to drive inflammation in various inflammatory disease. While clinical studies have demonstrated altered microbiome in patients with pancreatitis, the role of morphine induced modulation of gut microbiome and its impact on severity of acute and chronic pancreatitis has not been studied till date. In the current grant, we will evaluate the hypothesis that morphine worsens pancreatitis-induced local and systemic injuries by inducing dysbiosis. In specific aim 1 we will elucidate the role of morphine-induced dysbiosis in increasing severity of AP. In specific aim 2 we will elucidate the mechanism by which morphine-induced dysbiosis leads to modulation of inflammation in AP. Specifically the role of neutrophilic and macrophage dysfunction and the role of TLR-2 dependent processes will be evaluated. Finally, in specific aim 3, we will evaluate the role and mechanism of opioid induced dysbiosis in worsening of CP. We will also compare various opioids, with respect to their effect on severity of acute/chronic pancreatitis and we hope to translate these findings into clinical trials for identification of the safer opioid. In light of the current opioid crisis and increasing incidence of pancreatitis, these findings will pave the way for strategies that will counteract the deleterious effects of opioid use in worsening pancreatitis outcomes. Modulation of gut microbiome with probiotics may lead to alleviation of harmful effects of opioids in AP/CP.